Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

  title={Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death},
  author={Jianjin Shi and Yue Zhao and Kun Wang and Xuyan Shi and Yue Wang and Huanwei Huang and Yinghua Zhuang and Tao Cai and Fengchao Wang and Feng Shao},
Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. [] Key Method Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd−/− cells…

Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin

It is shown that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis, suggesting that casp enzyme activation can trigger necrosis by cleaving G SDME and offer new insights into cancer chemotherapy.

SERPINB1-mediated checkpoint of inflammatory caspase activation

The results reveal that SERPINB1 acts as a vital gatekeeper of inflammation by restraining neutrophil serine proteases and inflammatory caspases in a genetically and functionally separable manner.

Immunology: Caspase target drives pyroptosis

Two groups report that cleavage of the caspase substrate gasdermin D is sufficient to trigger pyroptosis, a form of programmed necrotic cell death, and are protected from a lethal dose of lipopolysaccharide.

The killer protein Gasdermin D

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Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor

A GSDMD-derived inhibitor, N-acetyl-Phe-Leu-Thr-Asp-chloromethylketone (Ac-FLTD-CMK), inhibits G SDMD cleavage in vitro and suppresses pyroptosis downstream of both canonical and noncanonical inflammasomes, as well as reduces IL-1β release following activation of the NLRP3 inflammaome in macrophages.

Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis




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Non-canonical inflammasome activation targets caspase-11

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Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria

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Inflammatory Stimuli Regulate Caspase Substrate Profiles*

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Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock

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Pyroptotic cell death defends against intracellular pathogens

This review focuses on molecular and morphological characteristics of pyroptosis and the individual inflammasomes and their contribution to defense against infection in mice and humans.